Dysfunctional platelet glycoprotein IIb/IIIa associated with a platelet release defect: a family study

We are reporting on a 36-year-old white female with a bleeding history attributed to dysfunctional platelet glycoprotein IIb/IIIa (GPIIb/IIIa) and a coexisting platelet release defect. Platelet aggregation studies (PAS) revealed markedly diminished to absent responses to ADP, epinephrine, collagen and arachidonic acid; the ristocetin response was normal. ATP content was normal with poor release to the agonists as measured by luminescent technique. DDAVP infusion shortened bleeding time from 13.5 min to 8.0 and 12 min (at 1 and 2 hours). Flow cytometry and immunoblotting revealed normal amounts of GPIIb and diminished GPIIIa (50% of control). Using a previously reported ELISA which measures the binding of GPIIb/IIIa to immobilized fibrinogen, the patient's platelet extract showed no binding to fibrinogen. Both the father and mother were found to have decreased PAS responses and normal amounts of GPIIb/IIIa determined by both Western blot and flow cytometry. However, the ELISA showed decreased binding of their GPIIb/IIIa to fibrinogen (71% and 62% as compared to controls, respectively). The patient's dysfunctional fibrinogen receptor was clearly demonstrated by the ELISA. The parents had moderately reduced GPIIb/IIIa function in this assay, but they did not demonstrate a reduced GPIIIa as was noted in the patient. The parents' PAS indicated a platelet release defect. These findings suggest an inherited platelet release defect and a dysfunctional GPIIIa. The partial response to DDAVP would be compatible with the presence of a platelet release defect.